Downregulation of nutrition sensor GCN2 in macrophages contributes to poor wound healing in diabetes.

Poor skin wound healing, which is common in patients with diabetes, is related to imbalanced macrophage polarization. Here, we find that nutrition sensor GCN2 (general control nonderepressible 2) and its downstream are significantly upregulated in human skin wound tissue and mouse skin wound macrophages, but skin wound-related GCN2 expression and activity are significantly downregulated by diabetes and hyperglycemia. Using wound healing models of GCN2-deleted mice, bone marrow chimeric mice, and monocyte-transferred mice, we show that GCN2 deletion in macrophages significantly delays skin wound healing compared with wild-type mice by altering M1 and M2a/M2c polarization. Mechanistically, GCN2 inhibits M1 macrophages via OXPHOS-ROS-NF-κB pathway and promotes tissue-repairing M2a/M2c macrophages through eukaryotic translation initiation factor 2 (eIF2α)-hypoxia-inducible factor 1α (HIF1α)-glycolysis pathway. Importantly, local supplementation of GCN2 activator halofuginone efficiently restores wound healing in diabetic mice with re-balancing M1 and M2a/2c polarization. Thus, the decreased macrophage GCN2 expression and activity contribute to poor wound healing in diabetes and targeting GCN2 improves wound healing in diabetes.

FABP5 Deficiency Impaired Macrophage Inflammation by Regulating AMPK/NF-κB Signaling Pathway.

Fatty acid binding protein 5 (FABP5) is mainly involved in the uptake, transport, and metabolism of fatty acid in the cytoplasm, and its role in immune cells has been recognized in recent years. However, the role of FABP5 in macrophage inflammation and its underlying mechanisms were not fully addressed. In our study, the acute liver injury and sepsis mouse models were induced by i.p. injection of LPS and cecal contents, respectively. Oleic acid (0.6 g/kg) was injected four times by intragastric administration every week, and this lasted for 1 wk before the LPS or cecal content challenge. We found that myeloid-specific deletion of FABP5 mitigated LPS-induced acute liver injury with reduced mortality of mice, histological liver damage, alanine aminotransferase, and proinflammatory factor levels. Metabolic analysis showed that FABP5 deletion increased the intracellular unsaturated fatty acids, especially oleic acid, in LPS-induced macrophages. The addition of oleic acid also decreased LPS-stimulated macrophage inflammation in vitro and reduced acute liver injury in LPS-induced or cecal content-induced sepsis mice. RNA-sequencing and molecular mechanism studies showed that FABP5 deletion or oleic acid supplementation increased the AMP/ATP ratio and AMP-activated protein kinase (AMPK) activation and inhibited the NF-κB pathway during the inflammatory response to LPS stimulation of macrophages. Inhibiting AMPK activation or expression by chemical or genetic approaches significantly rescued the decreased NF-κB signaling pathway and inflammatory response in LPS-treated FABP5-knockout macrophages. Our present study indicated that inhibiting FABP5 or supplementation of oleic acid might be used for the treatment of sepsis-caused acute liver injury.

Online responses to the ending of the one-child policy in China: implications for preconception care.

AIM: A critical analysis of online public postings in response to the news about the ending of China's one-child policy was conducted. The specific study aims were to 1) identify the dominant public discourse in response to the news about the ending of the one-child policy and the beginning of the new two-child policy, and 2) explore implications for preconception care from the public discourse. MATERIAL AND METHODS: Data sources were 10 top-ranked, online news media sites in China, including one Hong Kong-based media site. Selected online sites announced the news about the ending of the one-child policy on 29 October 2015. Online postings associated with the first news release of each online media site before midnight of 29 October were collected and analyzed. Critical discourse analysis was used for data analysis. RESULTS: Three main discourse concepts were identified. The online postings referenced the concepts of cost, generation, and timing with regard to the ending of the one-child policy and the beginning of the new two-child policy. Each concept represents an aspect of the public's view of preconception care, particularly interconception care, in China. DISCUSSION: These findings suggest that the change in the family planning policy may not result in a huge surge in the population in a short period of time, as some may opt not to have a second child. Nonetheless, there is an urgent need to incorporate interconception care into various health initiatives, as it is a time-sensitive choice for many couples to have a second child.